The rational design of cell-culture medium originated with Harry Eagle in 1955 when he began culturing cells in what would eventually become the progenitor of Eagles Medium (1). In subsequent decades, suppliers established a commercial market for the development and supply of cell-culture media. Over the next 45 years, these suppliers brought significant innovation to this field, including introducing the first serum-free medium, pioneering the creation of new media formats, and enabling many of the current high titer cell-culture processes. As the value of products derived from mammalian cells exponentially increased, so too has the demand for medium to culture cells. Today, cell-culture media for biological manufacturing represents a sizable market of more than $500 million, but more impressive is the cumulative value of therapeutic products enabled by these reagents, which totals more than $35 billion (2). Given the importance of these reagents, major suppliers, drug manufacturers, and other biotech companies continue to make significant investments to improve their cell-culture media platforms. Despite the tremendous value created by cell-culture media and the investment poured into research and development, this field remains a rather immature territory for efficient outsourcing models.

This article addresses some of the key issues that a company needs to think about when deciding to outsource development of a cell-culture medium. An outsourcing partner who understands these issues can provide guidance that will allow for informed choices about the sponsor's project goals.

Clearly defined technical goals

The first place to start when considering outsourcing is the technical goals of the project. Project expectations can vary widely, even among members of the same team; therefore such expectations need to be fully vetted, and priorities need to be set during the preliminary outsourcing discussions. The specified goals will ultimately define the technical approach for the project. While multiple goals can be designed into a project, budget and time constraints likely will force both parties to set priorities.

For example, a project goal might be to improve process consistency by removing undefined components (e.g., hydrolysates) from the production medium (3). If this is the case, then targeting productivity improvements should also be considered as a separate development initiative because a developer would likely use a different technical strategy for eliminating hydrolysates than they would follow for improving cell productivity. In fact, these two particular goals can appear to be competing if a cell-culture medium is not properly balanced (4). Likewise, a development project aiming to optimize a medium for a specific clone will look significantly different from a project where the primary technical goal is to develop a platform medium that works across multiple products and multiple clones. In the latter case, a developer is often faced with selecting criteria that work best across multiple clones at the sacrifice of performance of any single clone.

Figure 1. Commercial scale-up considerations should be part of any custom medium development. (All Figures are Courtesy of the Authors)

Finally, within the technical scoping of the project it is important that the medium developed can ultimately be manufactured at a scale and in a format that will support commercial production (see Figure 1). Beyond production considerations, the developed medium will also become part of your chemistry, manufacturing, and controls (CMC) regulatory submission. It is therefore essential to have the requisite quality controls (i.e., process validation, release specifications, stability, and shipping robustness) to fulfill regulatory filing requirements. This final aspect of technical scoping is often overlooked by research scientists; however, a medium-development partner should frame these considerations to fit within the sponsor's overall technical strategy.

In defining the overall technical goals, it is important to understand the starting point for development, not only in terms of the medium one is starting with, but also in terms of the quality of the cell line and the expected yield. Regarding the medium, the goals one sets for optimizing an in-house medium that one has worked with for several years will likely be much more specific compared with a vendor's catalog product that has been minimally optimized. Likewise, the technical approach for a robust cell line with expected high yields will not be the same as a project designed to salvage a low-producing cell line where any improvement will be welcomed. The factors described above relating to the medium starting point and the quality of the cells (as well as the expected yield) will determine how substantial a development effort is needed (and therefore the time and cost of the program).